Advertisement

Regulation of HIV-1 Gene Expression by the Tat Protein and the TAR Region

  • Michael F. Laspia
  • Shobha Gunnery
  • Mark Kessler
  • Andrew P. Rice
  • Michael B. Mathews
Part of the GWUMC Department of Biochemistry Annual Spring Symposia book series (GWUN)

Abstract

In addition to the structural genes gag, pol and env, the HIV family of human retroviruses encodes a number of novel regulatory genes (reviewed by Varmus, 1988, Cullen and Green, 1989; Pavalkis and Felber, 1990). One of these, the tat gene, is essential for viability and encodes a trans-acting regulator of HIV gene expression (Arya et al., 1985; Sodroski et al., 1985b). A cis-acting element in the long terminal repeat (LTR), called TAR, that is located downstream of the site of transcription initiation is required for Tat transactivation (Rosen et al., 1985; Jakobovits et al., 1988; Hauber and Cullen, 1988; Selby et al., 1989). The untranslated leader formed by transcription of TAR and present at the 5′ end of all HIV-1 mRNAs is capable of forming a stem and loop structure (Muesing et al., 1987). Recent studies indicate that at least one role for TAR RNA in gene regulation is to provide a binding site for Tat in the vicinity of the HIV-1 promoter (Southgate et al., 1990; Selby and Peterlin, 1990; Berkhout et al., 1990). The exact mechanism of Tat stimulation of HIV-1 gene expression remains controversial (Sharp and Marciniak, 1989). While the primary effect appears to be transcriptional, evidence has also been provided for additional or even predominant posttranscriptional effects.

Keywords

Human Immunodeficiency Virus Human Immunodeficiency Virus Type Long Terminal Repeat Recombinant Adenovirus Transcription Rate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Arya, S. K., Guo, C., Josephs, S. J., and Wong-Staal, F., 1985, Trans-activator gene of human T-lymphotropic virus type III ( HTLV-III ), Science 229: 69.Google Scholar
  2. Braddock, M., Chambers, A., Wilson, W., Esnouf, M. P., Adams, S. E., Kingsman, A. J. and Kingsman, S. M., 1989, HIV-1 Tat “activates” presynthesized RNA in the nucleus, Cell 58: 269.PubMedCrossRefGoogle Scholar
  3. Berk, A. J., 1986, Adenovirus promoters and E1A transactivation. Ann. Rev. Genet. 20: 45.Google Scholar
  4. Berkhout, B., Gatignol, A., Rabson, A. B., and Jeang, K.-T., 1990, TAR-independant activation of the HIV-1 LTR: evidence that Tat requires specific regions of the promoter, Cell 62: 757.PubMedCrossRefGoogle Scholar
  5. Cullen, B. R., 1986, Trans-activation of human immunodeficiency virus occurs via a bimodel mechanism, Cell 46: 973.PubMedCrossRefGoogle Scholar
  6. Cullen, B. R., and Greene, W.C., 1989, Regulatory pathways governing HIV-1 replication, Cell 58: 423.PubMedCrossRefGoogle Scholar
  7. Cullen, B. R., and Greene, W.C., 1989, Regulatory pathways governing HIV-1 replication, Cell 58: 423.PubMedCrossRefGoogle Scholar
  8. Edery, I., Petryshyn, R., and Sonenberg, N., 1989, Activation of double-stranded RNA-dependent kinase (dsI) by the TAR region of HIV-1 mRNA: a novel translational control mechanism, Cell 56: 303.PubMedCrossRefGoogle Scholar
  9. Feinberg, M. B., Jarrett, R. F., Aldovini, A., Gallo, R. C., and Wong-Staal, F., 1986, HTLV-111 expression and production involve complex regulation at the levels of splicing and translation of viral RNA, Cell 46: 807.PubMedCrossRefGoogle Scholar
  10. Greenberg, M. E., and Ziff, E. B., 1984, Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene, Nature 311: 433.PubMedCrossRefGoogle Scholar
  11. Greenberg, M. E., and Ziff, E. B., 1984, Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene, Nature 311: 433.PubMedCrossRefGoogle Scholar
  12. Hauber, J., Perkin, A. Heimer, E. P., and Cullen, B. R, 1987, Trans-activation of human immunodeficiency virus gene expression is mediated by nuclear events, Proc. Natl. Acad. Sci. USA 84: 6364.Google Scholar
  13. Hauber, J., and Cullen, B. R., 1988, Mutational analysis of the trans-activationresponsive region of the human immunodeficiency virus type I long terminal repeat. J. Virol. 62: 673.PubMedGoogle Scholar
  14. Jakobovits, A., Smith, D. H., Jakobovits, E. B., and Capon, D. J., 1988, A discrete element 3’ of human immunodeficiency virus 1 (HIV-1) and HIV-2 mRNA initiation sites mediates transcriptional activation by an HIV-1 trans activator, Mol. Cell. Biol. 8: 2555.Google Scholar
  15. Jeang K-T, Shank, P. R., and Kumar, A., 1988, Transcriptional activation of homologous viral long terminal repeats by the human immunodeficiency virus type 1 or the human T-cell leukemia virus type 1 tat proteins occurs in the absence of de novo protein synthesis, Proc. Natl. Acad. Sci. USA 85: 8291.Google Scholar
  16. Jones, N. C., Rigby, P. J., and Ziff, E. B., 1988, Trans-acting protein factors and the regulation of eukaryotic transcription: lessons from studies on DNA tumor viruses, Genes and Devel. 2: 267.CrossRefGoogle Scholar
  17. Kao, S.-Y., Calman, A. F., Luciw, P. A., and Peterlin, B. M., 1987, Anti-termination of transcription within the long terminal repeat of HIV by the tat gene product, Nature 330: 489.PubMedCrossRefGoogle Scholar
  18. Kessler, M., and Mathews, M. B., The mechanism of transactivation by Tat of HIV-1directed transcription is determined by the basal promoter activity, manuscript in preparation.Google Scholar
  19. Kitajewski, J., Schneider, R. J., Safer, B, Munemitsu, S. M, Samuel, C. E., Thimmappaya, B., and Shenk, T., 1986, Adenovirus of VA1 RNA antagonizes the antiviral action of interferon by preventing activation of the interferon-induced eIF-2a kinase, Cell 45: 195.PubMedCrossRefGoogle Scholar
  20. Laspia, M. F., Rice, A. P., and Mathews, M. B., 1989, HIV-1 Tat protein increases transcriptional initiation and stabilizes elongation, Cell 59: 283.PubMedCrossRefGoogle Scholar
  21. Laspia, M. F., Rice, A. P., and Mathews, M. B., 1989, HIV-1 Tat protein increases transcriptional initiation and stabilizes elongation, Cell 59: 283.PubMedCrossRefGoogle Scholar
  22. Maran, A., and Mathews, M. B., 1988, Characterization of the double-stranded RNA implicated in the inhibition of protein synthesis in cells infected with a mutant adenovirus defective for VA RNA1, Virol 164: 106.CrossRefGoogle Scholar
  23. Mellits K. H., and Mathews, M. B., 1988, Effects of mutations in stem and loop regions on the structure of adenovirus VA RNA1, EMBO J. 7: 2849.Google Scholar
  24. Muesing, M. A., Smith, D. H., and Capon, D. J., 1987, Regulation of mRNA accumulation by human immunodeficiency virus trans-activator protein, Cell 48: 691.PubMedCrossRefGoogle Scholar
  25. Nabel, G., and Baltimore, D., 1987, An inducible transcription factor activates expression of human immunodeficiency virus in T-cells, Nature 326: 711.PubMedCrossRefGoogle Scholar
  26. O’Malley, R. P., Mariano, T. M., Siekierta, J., and Mathews, M. B., 1986, A mechanism for the control of protein synthesis by adenovirus VA RNA1, Cell 44: 391.PubMedCrossRefGoogle Scholar
  27. O’Malley, R. P., Duncan, R. F., Hershey, J. B. and Mathews, M. B., 1989, Modification of protein synthesis initiation factors and the shut-off of host protein synthesis in adenovirus-infected cells, Virol. 168: 112.CrossRefGoogle Scholar
  28. Parkin, N. T., Cohen, E. A., Darveau, A., Rosen, C., Haseltine, W. and Sonenberg, N., 1988, Mutational analysis of the 5’ non-coding region of human immunodeficiency virus typel: effects of secondary structure on translation, EMBO J. 7: 2831.Google Scholar
  29. Pavlakis G. N., and Felber, B. K, 1990, Regulation of expression of human immunodeficiency virus, New Biol. 2: 20.PubMedGoogle Scholar
  30. Peterlin, B. M., Luciw, P. A., Barr, P. J., and Walker, M. D., 1986, Elevated levels of mRNA can account for the trans-activation of human immunodeficiency virus, Proc. Natl. Acad. Sci. USA 83: 9734.Google Scholar
  31. Pomerantz, R. J., Trono, D., Feinberg, M. B., and Baltimore, D., 1990, Cells nonproductively infected with HIV-1 exhibit an aberrant pattern of viral RNA expression: a molecular model for latency, Cell 61: 1271.PubMedCrossRefGoogle Scholar
  32. Proud, C., G., 1986, Guanine nucleotides, protein phosphorylation and the control of translation, TIBS 11: 73.Google Scholar
  33. Rice, A. P., and Mathews, M. B., 1988, Transcriptional but not translational regulation of HIV-1 by the tat gene product, Nature 332: 551.PubMedCrossRefGoogle Scholar
  34. Rice, A. P., and Mathews, M. B., 1988b, Trans-activation of the human immunodeficiency virus long terminal repeat sequences, expressed in an adenovirus vector, by the adenovirus E1A 13S protein, Proc. Natl. Acad. Sci. USA 85: 4200.Google Scholar
  35. Robertson, H. D. and Hunter, T., 1975, Sensitive methods for the detection and characterization of double helical ribonucleic acid, JBC 250: 418.Google Scholar
  36. Rosen, C. A., Sodroski, J. G., and Haseltine, W. A., 1985, The location of cis-acting regulatory sequences in the human T cell lymphotropic virus type III ( HTLVIIULAV) long terminal repeat, Cell 41: 813.Google Scholar
  37. Rosen, C. A., Sodroski, J. G., Goh, W. C., Dayton, A. I., Lippe, J., and Haseltine, W. A., 1986, Post-transcriptional regulation accounts for the trans-activation of the human T-lymphotropic virus type III, Nature 319: 555.PubMedCrossRefGoogle Scholar
  38. Rosen, C. A., Sodroski, J. G., Goh, W. C., Dayton, A. I., Lippe, J., and Haseltine, W. A., 1986, Post-transcriptional regulation accounts for the trans-activation of the human T-lymphotropic virus type III, Nature 319: 555.PubMedCrossRefGoogle Scholar
  39. Sadaie, M. R., Benter, T., and Wong-Staal, F., 1988, Site-directed mutagenesis of two trans-regulatory genes (tat-III, trs) of HIV-1, Science 239: 910.PubMedCrossRefGoogle Scholar
  40. Sanchez-Pescador, R., Power, M. D., Barr, P. J., Steimer, K. S., Stempein M. M., Brown-Shimer, S. L., Gee, W. W., Renard, A., Randolph, A., Levy, J. A., Dina, D., and Luciw, P. A., 1985, Nucleotide sequence and expression of an AIDS-associated retrovirus (ARV-2), Science 227: 484.PubMedCrossRefGoogle Scholar
  41. Selby, M. J., Bain, E. S., Luciw, P. A., and Peterlin, B. M., 1989, Structure, sequence, and position of the stem-loop in tar determine transcriptional elongation by tat through the HIV-1 long terminal repeat, Genes and Devel. 3: 547.CrossRefGoogle Scholar
  42. Selby, M. J., and Peterlin, B. M., 1990, Trans-activation by HIV-1 Tat via a heterologous RNA binding protein, Cell 62: 769.PubMedCrossRefGoogle Scholar
  43. Siekevitz, M., Josephs, S. F., Dukovich, M., Peffer, N., Wong-Staal, F. W., and Greene, W. C., 1987, Activation of the HIV-1 LTR by T cell mitogens and the trans-activator protein of HTLV-1. Science238: 1575.Google Scholar
  44. SenGupta, D. N., and Silverman, R. H., 1989, Activation of interferon-regulated dsRNA-dependent enzymes by human immunodeficiency virus-1 leader RNA, Nucl. Acid Res. 17: 969.Google Scholar
  45. Sharp P. A., and Marciniak, R. A., 1989, HIV TAR: An RNA enhancer? Cell 59: 229.PubMedCrossRefGoogle Scholar
  46. Sodroski, J., Rosen, C., Wong-Staal, F., Salahuddin, S. K., Popovic, M., Arya, S., Gallo,R. C., and Haseltine, W. A., 1985a, Trans-acting transcriptional regulation of human T-cell leukemia virus type III long terminal repeat, Science 227: 171.Google Scholar
  47. Sodroski, J. G., Patarca, R., Rosen, C., Wong-Staal, F., and Haseltine, W., 1985b, Location of the trans-activation region on the genome of human T-cell lymphotropic virus type III, Science 229: 74.PubMedCrossRefGoogle Scholar
  48. Southgate, C., Zapp, M. L., and Green, M. R., 1990, Activation of transcription by HIV- 1 Tat protein tethered to nascent RNA through another protein, Nature 345: 640.PubMedCrossRefGoogle Scholar
  49. Tong-Starksen, S.E., Luciw, P.A., and Peterlin, B.M., 1987, Human immunodeficiency virus long terminal repeat responds to T-cell activation signals. Proc. Natl. Acad. Sci. USA 84: 6845.Google Scholar
  50. Varmus, H., 1988, Regulation of HIV and HTLV gene expression, Genes and Devel. 2: 1055.CrossRefGoogle Scholar
  51. Weeks, K. M., Ampe, C., Schultz, S. C., Steitz, T. A., and Crothers, D. M., 1990, Fragments of the HIV-1 Tat protein specifically bind TAR RNA, Science 249, 1281 1285.Google Scholar
  52. Wright, C. M., Felber, B. K., Paskalis, H., and Pavlakis, G. N., 1986, Expression and characterization of the trans-activator of HTLV-III/LAV virus, Science 234: 988.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Michael F. Laspia
    • 1
  • Shobha Gunnery
    • 1
  • Mark Kessler
    • 1
  • Andrew P. Rice
    • 1
  • Michael B. Mathews
    • 1
  1. 1.Cold Spring Harbor LaboratoryCold Spring HarborNew YorkUSA

Personalised recommendations